This invention relates to various R-NSAID esters and their use in the treatment of illness and disease.
Neoplastic diseases are conditions in which abnormal proliferation of cells results in a mass of tissue called a neoplasm or tumor. Neoplasms have varying degrees of abnormalities in structure and behavior. Some neoplasms are benign while others are malignant or cancerous. An effective treatment of neoplastic disease would be considered a valuable contribution to the search for cancer preventive or curative procedures.
The gastrointestinal tract, including the rectum and colon, is lined with epithelial cells, which have a high proliferation rate. The lining of the colon, in particular, made up of columnar rows of epithelial cells, is characterized by a series of indentations or crypts. Epithelial cells in the bottom regions of the crypts proliferate and move upward toward the tops of the crypts. In the normal colon, the proliferation region of the large intestine normally occupies the basal or deeper three-quarters of the crypts. A relationship has been observed between the expansion of cell proliferation zones to the upper regions of the crypts and colon cancer. See M. Lipkin, “Biomarkers of Increased Susceptibility to Gastrointestinal Cancer: New Application to Studies of Cancer Prevention in Human Subjects,”Cancer Research, Vol. 48, pp. 235–245 (Jan. 15, 1988).
Cancer of the colon is common in the western world and is an important cause of morbidity and mortality, having an incidence of about 5% in the U.S. population. As with other types of cancers, cancers of the gastrointestinal tract, including colon cancer, are characterized by abnormal development in cell proliferation and differentiation in the gastrointestinal tract.
There has been an intensive search for chemopreventative agents for all individuals at risk for colon cancer and other gastrointestinal cancers, particularly individuals over the age of 45. One class of potentially therapeutically useful compounds is the non-steroidal anti-inflammatory drugs (“NSAIDs”). NSAID's, presently in common use as anti-inflammatory agents and as analgesics, are known to have neoplasia chemoprevention and other anti-neoplastic benefits. Physiologically, NSAID's are known to inhibit the biosynthesis of prostaglandins by the inhibition of the cyclooxygenase enzyme, which is ubiquitous in mammalian tissues. See Buckley et al., Drugs, 39(1):86–109 (1990). The role of NSAID's in prevention of colorectal cancer is discussed in Heath, et al., “Nonsteroidal Antiinflammatory Drugs and Human Cancer,” Cancer, Vol. 74, No. 10, pp. 2885–2888 (Nov. 15, 1994).
However, the use of NSAID's in colon cancer prevention has been associated with severe undesirable side effects, which include gastrointestinal, renal and hepatic toxicities, as well as increases in bleeding times due to disruption of platelet function (e.g., thrombocytopenia), and prolongation of gestation due to uterine effects. Another serious side effect associated with the use of certain NSAID's is leukopenia (decreased white cell count in the blood), and consequent agranulocytosis.
Agranulocytosis is a life-threatening condition that develops very rapidly, and that is difficult to detect even with periodic white-cell counts. The leukopenia/agranulocytosis syndrome has been described for several NSAID's, such as indomethacin, ketoprofen, and ibuprofen. Indeed, such NSAID's are contraindicated in patients whose immune systems are compromised by HIV infection, chemotherapy, ionizing irradiation, corticosteroids, immunosuppressives, etc., or by such conditions as emphysema, bronchiectasis, diabetes mellitus, leukemia, burns and the like. A recent review of the adverse effects of NSAID's is Borda, et al., “NSAIDs: A Profile of Adverse Effects,” Hanley and Belfus, Inc., Philadelphia, Pa., 1992.
The most recent epidemiologic survey showing that both aspirin and NSAID's confer protection against colon cancer is Peleg, et al., “Aspirin and Nonsteroidal Anti-inflammatory Drug Use and the Risk of Subsequent Colorectal Cancer,” Arch. Intern. Med., Vol. 154, pp. 394–400 (Feb. 28, 1994). This reference identifies a causal relationship between the use of NSAID's, such as indomethacin, sulindac and peroxicam, and prevention of cancer of the large bowel and rectum. A risk benefit analysis is suggested, however, due to the severe potential gastrointestinal and renal side effects, particularly in the elderly.
The standard treatment for colon cancer currently consists of the administration of a known cancer-fighting agent, 5-fluorouracil in combination with the anthelmintic levamisole. No improvement in survival among colon cancer patients was shown when 5-fluorouracil was administered alone. The addition of levamisole, which is known to stimulate the immune system and increase T-cell count, showed improved survival rate among these patients. See Moertel, et al., “Levamisole and Fluorouracil for Adjuvant Therapy of Resected Colon Carcinoma,” N Engl J Med 1990; 322:352–358.
Many NSAID's exhibit molecular chirality, and thus have R- and S-enantiomers. Such compounds typically are produced as racemic mixtures, which subsequently may be separated into the individual enantiomers.
The enantiomers of several 2-arylpropionic acid NSAID's are discussed in Yamaguchi, et al., Nippo Yakurigaku Zasshi, 90:295–302 (1987). Yamaguchi, et al. state that the S-enantiomers of 2-arylpropionic acids have 15–300 times higher prostaglandin synthetase inhibitory activities than the R-enantiomers in the rat. Caldwell, et al., Biochem. Pharmacol. 37: 105–114 (1988) allege that “at best, the R-isomers of 2-arylpropionic acids function as prodrugs for the therapeutically active S-forms” when the racemic drug is administered and, thus, add to both the therapeutic and toxic effects of the active S-enantiomers. Caldwell, et al. further contend that “at worst, the R-enantiomers are undesirable impurities in the active drug” causing difficulties due to non-stereoselective toxicity. The authors indicate that the use of the S-isomers alone should provide safer and more effective use of this class of drugs.
Similarly, it has been generalized that the pharmacokinetics of the enantiomers of 2-arylpropionic acids are different due, at least in part, to the unidirectional metabolic inversion of the R- to the S-enantiomer. However, it has been found that this interconversion depends on the particular compound and the particular species in which it is administered. Jamali, Eur. J. Drug Metabolism Pharmaco. 13: 1–9(1988).
Because of the toxicity and side effects previously described, many NSAID's are no longer in use in human medicine as analgesics. Some of these NSAID's include tiaprofenic acid, suprofen, carprofen, pirprofen and indoprofen.
A need has been identified for new formulations of NSAID's that are effective in treating neoplastic disease including colorectal and other cancers and are more tolerable with regard to gastrointestinal toxicity. Thus, it would be particularly desirable to provide compositions and methods for the prevention of neoplasia and colorectal cancer but without the aforementioned disadvantages.
Another disease for which effective treatment is needed is cystic fibrosis. Cystic fibrosis (CF) is a heritable disease that follows an autosomal recessive pattern of transmittance. It is the most common lethal genetic disease in the United States. The approximate frequency in Caucasians is 1 in 2000. Cystic fibrosis is characterized by abnormal eccrine and exocrine gland function. In particular, mucous glands produce viscous secretions that lead to chronic pulmonary disease, insufficient pancreatic and digestive function and abnormally concentrated sweat.
The most prominent theories of CF etiology focus on alterations in physiochemical properties of exocrine secretions, the regulation of exocrine gland secretions, electrolyte transport and abnormalities in serum. Typical presentations include early onset of respiratory symptoms such as colds, and recurrent respiratory infections later in life. CF patients show evidence of decreasing pulmonary function with time, and their sputum cultures often display S. aureus, P. aeruginosa and P. capacia. 
The major source of CF morbidity is pulmonary disease. More than 98% of CF patients die of either respiratory failure or pulmonary complications. Antibiotics are the key element in increasing survival. Prior to the 1950's, when modern antibiotics began to become available, patients typically survived for only a few years. At present, the medial survival age is 24. Consequently, stimulation of neutrophil function as a means of clearing bacterial foci is thought to be an appropriate focus of treatment; however, the resulting inflammatory response can lead to other complications.
It has been reported (M. W. Konstan, et al., New England J. Med. 1995; 332:848–854) that high doses of racemic ibuprofen in cystic fibrosis patients over a four-year period slows progression of the lung disease. However, gastrointestinal side effects due to the presence of S(+)-ibuprofen severely limit the chronic use of this therapy, particularly at high dose and as the racemate (see Wechter, W. J. J. Clin. Pharmacol. 1994; 34:1036–1042 and Wechter et al. Chirality 1993; 5:492–494). It is believed that high doses of racemic ibuprofen inhibits the influx of neutrophils to the alveolar crevices, while low doses increase the influx of neutrophils. The high doses employed in the Konstan study also appear to cause conjunctivitis and epistaxis.
Still another disease for which effective treatment is needed is dementia including Alzheimer's Disease (AD), which is a degenerative brain disorder associated with extensive loss of specific neuronal subpopulations and characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in varied races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect up to four million individuals in the United States alone. To date, AD has proven to be incurable, and presently causes up to 50,000 deaths yearly.
The brains of individuals with AD exhibit neuronal degeneration and characteristic lesions variously referred to as amyloidogenic plaques, vascular amyloid angiopathy, and neurofibrillary tangles. Large numbers of these lesions, particularly amyloidogenic plaques and neurofibrillary tangles, are generally found, in patients with AD, in several areas of the human brain important for memory and cognitive function. Smaller numbers of these lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not have clinical AD, as well as patients suffering from Down's Syndrome and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.
It is presently believed that progressive cerebral deposition of particular amyloidogenic proteins, beta-amyloid proteins (beta AP), play a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. Recently, it has been shown that beta AP are released from neuronal cells grown in culture and are present in cerebrospinal fluid (CSF) of both normal individuals and AD patients.
A possible correlation to the plaque pathology has been developed by several groups demonstrating the direct beta AP neurotoxicity toward cultured neurons. More recently, in addition to the direct neurotoxicity, an inflammatory response in the AD brain, perhaps elicited by beta AP, also contributes to the pathology of the disease. A limited clinical trial with the NSAID indomethacin exhibited a retardation in the progression of Alzheimer's dementia (Rogers, et al., Science, 266:1719–1720 (1993)).
Previous methods of treating AD are disclosed, for example, in U.S. Pat. No. 5,576,353 (use of N-propargyl-aminoindan compounds) and U.S. Pat. No. 5,552,415 (use of raloxifene and related compounds). A continuing need exists for effective methods for preventing, delaying, and treating AD.
Recently, a composition for use in preventing colorectal cancer and other neoplastic diseases, such as breast cancer was disclosed in U.S. Pat. Nos. 5,981,592 and 5,955,504. The composition includes an enantiomerically stable R-NSAID or a pharmaceutically acceptable salt thereof in an amount effective to elicit a chemopreventative effect. The composition is substantially free of the S-enantiomer of the R-NSAID. Therapeutic use of the composition is accompanied by reduced adverse side effects. A method of treating cystic fibrosis is also disclosed using the aforementioned composition. Furthermore, the composition was found useful in the treatment of Alzheimer's Disease.
A continuing need exists for compositions that are useful in the treatment of neoplastic disease, inflammation, cystic fibrosis, dementia, and the like. The compositions should allow for entry into tissue.